We will undertake the synthesis and evaluation in several selected enzyme systems of a series of pteridines, azapteridines, and related heterocyclic systems of potential pharmacological and biochemical utility. Included in the enzymatic studies will be a number of dihydrofolate reductase systems (from L1210 mouse leukemia, rat liver, L. casei, Trypanosoma cruzi, Trypanosoma brucei, and Dirofilaria immittis), mammalian liver aldehyde oxidases, rat liver phenylalanine hydroxylase, bovine adrenal tyrosine hydroxylase, bovine tryptophan hydroxylase, xanthine oxidase, aldehyde oxidase, and adenosine deaminase. Our target compounds for synthesis, designed on the basis of the pharmacological studies carried out thus far in the program, include 2,4-diaminopteridines and 7-azapteridines with multifunctional C-6 substituents (as biopterin and neopterin analogs), and a series of 2,4- diamino-6,7-(cycloalkyl)pteridines (certain homologs have been found to be very potent dihydrofolate reductase inhibitors). Our studies on the development and exploitation of new synthetic methodologies in heterocyclic chemistry will be continued. Our goal is the discovery of useful compounds for the treatment of neoplastic disease, certain hypertensive states, Parkinson's disease, and a variety of protozoal diseases, and for studies of drug metabolism.